Age-related hearing loss (presbycusis) is the most common neurodegenerative disease, afflicting nearly half of the population over 75 years of age. According to the National Council on Aging, presbycusis leads to decreased quality of life, can increase emotional distress such as sadness and depression, and leads to withdrawal from family, friends, and community. Current treatment options, which only a fraction of older adults with presbycusis receive, are primarily limited to hearing aids, which often fail to restore optima auditory function. We recently discovered that trimethadione and ethosuximide, two antiepileptic drugs that block T-type calcium channels, can effectively ameliorate noise-induced and age-related hearing loss in mice. Unfortunately, both drugs cause undesirable side effects at dosages used for epilepsy prophylaxis. Here, we propose two specific aims to translate our findings for potential use in humans. The studies in specific aim 1 will allow us to determine the pharmacodynamic properties of ethosuximide and related compounds against presbycusis. These experiments will provide structure-activity relationship information to facilitate chemical optimization of these compounds against presbycusis. The data will also address whether ethosuximide and related compounds can attenuate presbycusis at dosages lower than those prescribed when the drugs are used as anticonvulsants. In specific aim 2, we will develop combination therapies targeting both calcium and free radical pathways. Combination therapies will include one inhibitor of T-type calcium channels (either ethosuximide or zonisamide) plus one or two antioxidants (vitamin C or E). If a synergistic effect is discovered, the dosage of each compound can be reduced. We will also test whether the same combinations can prevent accelerated age-related hearing loss in mice exposed to noise at a young age. After treatment, quantitative histological analysis of cochleae will be used to identify cellular targets. A batteryof behavioral tests will be used to evaluate potential neurological side effects. We expect this project to result in new drugs or drug combinations that effectively mitigate presbycusis. Importantly, because we focus on the discovery of new uses for drugs already approved by the U.S. Food and Drug Administration, our work has the potential for rapid translation into clinical practice. Overall, this project represents an extraordinary opportunity that brings a multidisciplinary team together for the purpose of developing an effective drug-based intervention for presbycusis.